19 nor-deta2-androstene-17beta-ol and the esters thereof



United States Patent 3,239,542 19 NOR-A -ANDROSTENE-UB-OL AND THE ESTERSTHEREOF Albert Bowers, John Edwards, and James C. Orr, all of MexicoCity, Mexico, assignors, by mesne assignments, to Syntax Corporation, acorporation of Panama No Drawing. Filed Aug. 1, 1961, Ser. No. 128,361Claims priority, application Mexico, Feb. 7, 1961, 61,504, 61,505 17Claims. (Ci. 260-3975) The present invention relates to a new method forpreparing certain cyclopentanophenanthrene derivatives and to the use ofthe same as anabolic agents.

More particularly, it relates to a new method for preparing A-androsten-l7B-ol as well as the novel 19-nor- A -androsten-l7/3-ol, theNot-aliphatic hydrocarbon derivatives thereof as well as the esters ofsuch compounds.

The surprising discovery has been made that these compounds are potentanabolic agents having a very small androgenic activity; furthermore,they possess anti-estrogenic activity, lower the chloesterol level inthe blood and inhibit the excretion of gonadotro-pins by the pituitarygland. The 17a-alkenyl and l7at-alkynyl compounds further possessprogestational activity.

The anabolic-androgenic activity of these compounds has been measured,for example, in young male castrated rats, administering the compound byinjection and measuring the response of such treatment by the increasein weight of the ventral prostate, seminal vesicles and the levatoryanus muscle. The results of these tests indicate that these compoundspossess a very small androgenic activity, whereas the anabolic activityis much higher than the anabolic activity of testosterone.

Taking into account the biological activity of A -androsten-l7B-ol, ofits esters as well as of the corresponding 19-nor-derivatives, therehave been found many indications for the use of such compounds in humantherapy. The main applications in medical practice are those cases ofpatients with weakening diseases Where it is necessary to increase theprotein metabolism, a positive balance of nitrogen and a largerdeposition of calcium in the bone tissue. Within this field ofapplication fall all of the cases of deficient nutrition or growth,metastasic cancer, caquectizing chronic diseases, osteoporosis andpostoperatory handling of different surgery indications, as well asother diseases which produce a negative nitrogen balance.

The therapeutic dose for these compounds varies between 2 and 10 mg. perday, according to the age and the pathological state of the patient.

The novel compounds are administered by injection: A -androsten-17B-oland its l9-nor derivative in microcrystalline suspension and theiresters in oil solution, preferably using sesame oil as vehicle.

When a prolonged action is desired, there may be advantageouslyadministered a mixture of esters derived from carboxylic acids of 1 to12 carbon atoms, of dilferent chain length, such as for example amixture of the acetate and undecenoate of A -androsten-l7B-ol in oilsolution. A single injection of such preparation is suflicient toproduce the same action of several injections of the free compound or ofa single ester administered daily for several weeks;

Patented Mar. 8, 1966 "ice however, the required doses are generallyhigher than those indicated previously.

The method for preparing A -andr0sten-17fl-ol, its esters and thederivatives lacking the angular methyl group at C-l0 is illustrated bythe following sequence of reactions:

O R li R In the above formula, R represents hydrogen or methyl; Rrepresents hydrogen or an acyl radical derived from a carboxylic acid of1 to 12 carbon atoms, saturated or unsaturated, of straight, branched,cyclic, mixed aliphaticcyclic or aromatic chain, which may further besubstituted with functional groups such as hydroxy, alkoxy, nitro, aminoor halogen. Typical such esters are the acetate, propionate, caproate,enanthate, undecenoate, benzoate, trimethylacetate, t-butylacetate,phenoxyacetate, cyclopentylpropionate, aminoacetate andfi-chloropropionate.

Upon treatment of dihydroallotestosterone or an ester thereof (1),preferably the acetate with one molar equivalent of bromine in glacialacetic solution, at a temperature between 15 and 20 C., there isaiforded a 2a-bromoandrostan-17B-ol-3-one or its esters (II; R=methyl).The 2-bromo derivative is then reduced with a double metal hydride, suchas sodium borohydride, in a solvent inert to this reaction, preferablymethanol or dioxane, for a period of time between 5 and 18 hours, toproduce a mixture of Za-bromo-androstane-B,8,17B-diol and2abromo-androstane-3u,l7{3-diol (III; R methyl), with simultaneoushydrolysis of the l7-acyloxy group when the starting material employedis an ester of dihydroallotestosterone.

3 By heating at 89-90 C., the mixture of epimeric bromo hydrins withzinc dust in acetic acid, with stirring, for a period of time ofapproximately one hour, there is obtained A -androsten-17B-ol (IV;R=methyl).

In a similar manner, the process set forth above is applied to19-nor-dihydrotestosterone or its esters; thus, by

bromination of 19-nor-dihydroallotestosterone or an ester as Well as itsesters and the corresponding l9-nor-analogs.

are potent anabolic agents having a very small androgenic activity.

The novel compounds of the present invention containing a Hot-aliphatichydrocarbon group are represented by the following formula:

In the above formula, R and R have the same meaning as describedpreviously; R represents a lower alkyl group, that is an alkyl group ofless than 8 carbon atoms such as methyl, ethyl, propyl or butyl; a loweralkenyl group, that is, an alkenyl group of 2 to 6 carbon atoms such asvinyl, propenyl-(l), or butenyl-(l), or a lower alkynyl group of 2 to 6carbon atoms such as ethynyl, propynl or butynyl-( 1).

In accordance with the invention, by treatment of A -androsten-17-one orits 1 9-nor derivative with an alkyl, alkenyl or alkynyl magnesiumhalide such as methyl, ethyl, propyl, vinyl, ethynyl or propargylmagnesium bromide, there are obtained the corresponding l7a-alkyl,alkenyl or alkynyl derivatives of A -androsten- 175-01 and of 19-nor-A-androston-175-01.

Alternatively, the 17a-alkynyl substituted derivatives may be obtainedby treatment of A -androsten-17-one or 19-nor-A -androsten-17-one withsodium acetylide or potassium acetylide, or with the sodium or potassiumsalt of another lower alkine such as propine.

The 17a-alkenyl substituted derivatives may also be.

obtained from the 17a-alkynyl compounds by catalytic hydrogenation.

The novel compounds of the present invention containing the17tx-substituent are prepared by a process illustrated by the followingequation:

The treatment of the above mixture of p In the above formulas, R, R andR have the same meaning as set forth above.

In practicing the process outlined above, A -androsten 17-one, describedby Iriarte et al. in J. Org. Chem., 20, 542 (1955 is dissolved in anaromatic hydrocarbon such as benzene, toluene or Xylene, or any otherinert organic solvent such as ether or tetrahydrofuran, and treated witha Grignard reagent at the reflux temperature for a period of timefluctuating between 3 and 18 hours, or at room temperature for 15 to 24hours, under anhydrous conditions, to convert the 17-keto group into the17fi-hydroxy- 17u-alkyl, 17fi-hydroxy-17a-alkenyl or17/i-hydroxy-17aalkynyl grouping, according to the organometallic halideemployed for the reaction; Thus, by reaction with methyl magnesiumbromide, there is obtained Hot-methyl- A -androsten-17fl-ol, and bysimilar reaction with an ethyl, propyl, vinyl, ethinyl or propargylmagnesium halide, or any other Grignard reagent, there are produced therespective Hot-substituted A -androsten-lm-ol derivatives.

As has been set forth above, the 17a-alkynyl-17B- hydroxy-A -androstenesmay also be obtained by treating a benzene solution of 'A-androsten-17-one with sodium or potassium acetylide or with thesodiumorpotassium salt of any other alkyne. By partial hydrogenationofthe 17a-alkynyl-Alandrosten-1 7fl-hydroXy compounds, in the presenceof a palladium catalyst, such as' palladium on calcium carbonate, and.using an amine as solvent, preferably pyridine, there are obtained thecorresponding calkenyl derivatives.

By applying the process set forth above, to 19-nor-A androsten-17-one,which is in turn obtained by oxidation of 19-nor-A -androsten--01, thereare obtained the corresponding 170t-SllbStIt1ltCd derivatives lackingthe angular methyl group at C-10. Thus, by treatment of 19-nor-A-androsten-17-one with a Grignard reagent of the type set forth above,there are obtained the respective 17a-alkyl, 17u-a1keny1, and17a-alkynyl derivatives of;

By reacting the l7a-alkyl, 17a-alkenyl or 17ot-a1kynyl 1 derivatives ofA -androsten-17fi-ol and the corresponding 19-nor derivatives with theanhydride or chloride derived from a carboxylic acid of 1 to 12 carbonatoms, in benzene solution and in the presence of ,p-toluenesulfonicacid, there are obtained the esters of such compounds.

The following examples serve to illustrate but are not.

intended to limit the scope of the present invention:

Example I A solution of 5g. of the acetate ofdihydroallotestosw teronein 100 cc. ofracetic acid Wastreated dropwise under stirring at atemperature between '15 and 20 C. with a solution of 2.5 g. of bromine(1.1 molar equivalents) in 50 cc. of acetic acid. The solution wasstirred until it decolorized completely, then poured into ice cold saltsolution and the precipitate formed;was collected by filtration, washedwith Water to neutral, dried and recrystallized from acetone-hexane,thus yielding 3.9 g. of the acetate of 2u-bromodihydroal1otestosterone.vTo a solution of 3 g. ofthe above compound in 50 cc. of dioxane wasadded at room temperaturea solution of 3 g. of sodium borohydride in 10cc. of water and the mixture was kept standing overnight at roomtemperature; the excess of reagent was decomposed by the addition of 0.5

'cc. of acetic acid and the solution was concentrated to a small volumeunder vacuum; after pouring into water the product was extracted withseveral portions of ethyl acetate and the extract was washed with waterto neutral, dried over anhydrous sodium sulfate and evaporated todryness, thus furnishing a mixture of 2a-bromo-androstane3fi,17,B-dioland 2a-bromo-androstane-3a,17,8-diol, which was purified bychromatography on washed alumma.

A mixture of 2 g. of the above crude bromohydrin and 50 cc. of aceticacid was treated with 2 g. of zinc dust and then stirred for one hour at90 C. (steam bath). The zinc was removed by filtration through celiteand the filtrate was diluted with Water; the precipitate formed wascollected, well washed with water to neutral and dried under vacuum.Recrystallization from acetonehexane afforded 1.1 g. of A-androsten-17fl-0l.

Example 11 A solution of 1 g. of A -androsten-17p-ol in 4 cc. ofpyridine and 2 cc. of propionic anhydride was kept overnight at roomtemperature, then poured into Water and the precipitate formed wascollected and recrystallized from acetone-ether, thus giving thepropionate of A androsten-17fi-ol.

Example III By the same method of esterification described in thepreceding example, but using acetic, valeric, caproic, undecenoic andcyclopentylpropionic anhydrides as esterifying agents, there wereobtained the acetate, valerate, caproate, undecenoate andcyclopentylpropionate of A -androsten-17fl-ol.

Example IV The method of Example I was repeated, but using this time thefree dihydroallotestosterone, thus obtaining successivelyZa-bromoandrostan-17,8-ol-3-one, 2a-bromoandrostane-3,17,B-diol and A-androsten-17fi-ol, identical with the product obtained in such example.

Example V By following the method of Example I, but using as startingmaterial the acetate of 19-nor-di-hydroallotestosterone, there Wereobtained 2a-brcmo-19-nor-androstane-3,17/3-diol and l9-nor-A-androsten-175-01.

A mixture of 1 g. of the above compound, 5 cc. of pyridine and 2 cc. ofacetic anhydride was heated for 1 hour on the steam bath, poured intowater and the precipitate formed was collected, thus yielding theacetate of 19-nor-A -androsten-1713-01.

Example VI A solution of 500 mg. of 19-nor-A -androsten-175-01 in 2.5cc. of pyridine was treated with 1 cc. of benzoyl chloride and themixture was heated for 1 hour on the steam bath; after pouring intowater, the precipitate formed was collected and washed with water, thusgiving the benzoate of 19-nor-A -androsten-175-01.

Example VII Pharmaceutical composition containing the propionate of A-androsten-17B-ol in the form of injectable oil solution:

1 cc. contains: Mg. M-androsten-l7B-ol-pr0pionate 25.0Propyl-p-hydroxybenzoate (propyl-paraben U.S.P.) 1.0 Benzyl alcohol104.3 Sesame oil 805.0

Preparation: Place carefully weighed A -androsten-17B- 01 and thepr-opyl-paraiben in an adequate container which can be hermeticallyclosed. Add the benzyl alcohol and the sesame oil, sending down thesolid particles sticking to the sides of the container. Closehermetically and heat under stirring at 90 C. until all dissolves. Coolto 40-50 C. and filter through a Hormon EOP ultrafilter (Selas cells ofXFF porosity may also be employed). Seal with neoprene stoppers andsterilize at C. in a dry heat oven for 12 hours. Aseptically transfer toadequate containers according to the required doses. Finally sterilizethese containers at 125 C. for 12 hours for ampoule bottles, and for 2hours for ampoules.

The administration of this composition by injection produces a favorableanabolic effect, whereas the androgenic activity is very small.

Example VIII Pharmaceutical composition containing A -androsten- -01 inthe form of injectable suspension:

Distilled water 968.400

Preparatz'0n.A solution was obtained by dissolving sodium chloride,methyl p-hydroxybenzoate and propyl p-hydroxybenzoate in the distilledwater, which was then sterilized by filtration. 200 g. of such solutionwere used to dissolve the methyl cellulose and the sodium carboxymethylcellulose (solution B).

Solution B was transferred to a ball mill, the carefully weighed A-androsten-17fi-ol was added and the mixture sterilized for 1% hours inan autoclave at 120 C.; after cooling, the Tween 80 was added. Thesterile mixture thus obtained was stirred (rotary stirring) for 48 hoursat room temperature and the resulting suspension was quantitativelytransferred to a sterile container, then diluting with the rest ofsolution A (also sterile) and adjusting the pH to 6.8. Finally it wastransferred to 1 cc. ampoules under aseptic conditions. Each cubiccentimeter of this injectable suspension contains approximately 5 mg. ofA -androsten-17fl-ol.

The administration of this injectable suspension produces a favorableprotein balance, whereas the androgenic action is very small.

Example IX Pharmaceutical composition containing a mixture of esters ofA -androsten-17B-ol in the form of injectable oil solution:

1 cc. contains: Mg. Acetate of A -androsten-l7 8-ol 20 Valerate of A-androsten-175-ol 40 Undecenoate of A -androsten-17p-o1 120Propyl-para'oen U.S.P. 1.0 Benzyl alcohol 110 Sesame oil 775 The methodof preparation is the same as described in Example VII.

The administration of a single dose of this composition produces anitrogen retention for several weeks.

Example X A solution of 5 g. of A -androsten-17-one in 100 cc. ofanhydrous benzene free of thiophene was slowly added to 25 cc. of a 4 Nsolution of methyl magnesium bromide in ether and the mixture wasrefluxed under anhydrous conditions for 3 hours, cooled, cautiouslypoured into water and acidified with hydrochloric acid; the benzenelayer was separated and the aqueous phase was extracted several timeswith ethyl acetate; the organic extracts were combined with the benzenesolution and then washed to neutral, dried over anhydrous sodium sulfateand evaporated to dryness under reduced pressure. By crystallizationfrom acetone-hexane, there was obtained 17u-rnethy1- A -androsten17,8-01.

A mixture of 1 g. of the above compound, 40 cc. of acetic acid, 20 cc.of acetic anhydride and l g. of p-toluenesulfonic acid was kept at roomtemperature for 1 hour and then poured into water; after heating for 30minutes on the steam bath to hydrolyze the excess of reagent theprecipitate formed was collected and Washed with water to neutral, thusaffording the acetate of l7ot-methyl-A androsten-17B-ol.

Example XI By following the method of the preceding example, but usingethyl magnesium bromide and propyl magnesium bromide instead of methylmagnesium bromide as alkylating agents, the A -androsten-l7-one wasrespectively converted into 17u-ethyl-A -androsten-175-ol andl7a-propyl-A -androsten-175-01. The subsequent acetylation of thesecompounds with a mixture of acetic acid and acetic anhydride and in thepresence of p-toluenesulfonic acid yielded the corresponding acetates.

Example XII A solution of A -androsten-l7-one in 100 cc. of anhydrousether was added dropwise to a solution of propargyl magnesium bromide(prepared from 6.8 g. of propargyl bromide, 1.4 g. of magnesium and 200cc. of ether). The mixture was refluxed with stirring overnight, andthen cooled and poured into 500 cc. of a 5% solution of ammoniumchloride; the ether layer was separated and washed to neutral withwater, dried over anhydrous sodium sulfate and evaporated to drynessunder vacuum. Crystallization of the residue from methanol furnishedl7a-propargyl-A -androsten-l7fi-ol.

A solution of 1 g. of the above compound in cc. of benzene was mixedwith 2 cc. of propionic anhydride and 0.5 g. of p-toluenesulfonic acidand kept overnight at room temperature. The mixture was then dilutedwith water and stirred for 30 minutes in order to hydrolyze the excessof reagent; the benzene layer was separated, washed with 5% sodiumcarbonate solution and finally with water to neutral, dried overanhydrous sodium sulfate and evaporated to dryness under vacuum.Chromatography of the residue on washed alumina followed bycrystallization of the solid fractions from acetone-hexane afforded thepropionate of 17ot-propargyl-A -androsten- 175-01.

Example XIII A stirred solution of 10 g. of 19-nor-A -androsten-17fi-01, obtained in Example V, in 100 cc. of acetic acid was kept standingfor 1 hour at room temperature, poured into ice cold salt solution andthe precipitate formed was collected by filtration and washed with waterto neutral, thus yielding 19-nor-A -androsten-17-one, which was purifiedby crystallization from chloroform-methanol.

5 g. of the above compound was treated with methyl magnesium bromide, inaccordance with the method of Example X, to produce Not-methyl-19-nor-A-androstcn- 17,8-01.

Example XIV By following the method of Example X, but using ethyl,vinyl, ethinyl or propargyl' magnesium bromide, 19-nor-A-androsten-17-one was respectively converted into 17a-ethyl-19-nor-A-androsten-175-01, 17a-vinyl-19- nor-A -androsten-l7fl-ol, 17a-ethiny1-A-androsten-l75-01, and 17a-propargyl-19-nor-A -androsten-17,8-01.

8 Example XV A solution of 2 g. of A -androste'n-l7-one in 60 cc. of

anhydrous benzene was added under anatrnosphere of nitrogen to asolution of potassium t-amylate previously prepared from 1.4 g. ofpotassium and30 cc. of t-amyl alcohol. duced into the resulting mixturefor 40 hours and the solution was then poured into ice water andextracted several times with benzene. The combinedextract was washed toneutral and the organic solution was diied over anhydrous sodium sulfateand evaporated to dryness under vacuum. The residue was chromatographedon 50 times its weightof washed alumina and the crystalline fractionswere recrystallized from acetone-hexane, thus, yielding l7ot-ethiny1-A-androsten-17,8-01.

By following the method of esterification of Example X, there wasobtained the respective acetate.

Example XVI A solution of 2 got 17u-ethiny1-A -androsten-1713-01 in 50cc. of pyridine was hydrogenated at room temperature and atmosphericpressure in the presence of 0.6 g.

of 5% palladium on calcium carbonate catalyst (which.

had been previously reduced). When 1 molar equivalent of hydrogen hadbeen absorbed the catalyst was removed by filtration and the filtratewas evaporated to dryness under vacuum. The residue was dissolved inethyl acetate, washed with hydrochloric acid to completely remove thepyridine and finally with water to neutral, dried and concentrated to asmall volume- Crystallization from ethyl acetate-hexane afforded17a-vinyl-A -androsten- 17,8-01.

A mixture of500 mg. of the above compound, 25 cc. of benzene, 2 cc. ofcyclopentylpropionic anhydride: and 250 mg. of p-toluenesulfonic acidwas kept standing at room temperature for 48 hours, diluted with Water,stirred for 30 minutes to hydrolyze'the excess of reagent and thebenzene layer was separated, washed to' neutral, dried over anhydroussodium sulfate and evaporated to dryness. By crystallization of theresidue from acetoneether, there was obtained thecycl-opentylpropionate. of 17a-vinyl-A -androsten-17,8-01.

Example XVII By following the method of hydrogenation described in thepreceding example, 500 mg. of the propionate of l7a-propargyl-A-androsten-l7/3-ol was converted into l7ot-propenyl-A -androsten-17,8-01propionate.

Example X VIIIv In accordance with the method of esterification de-.scribed in Example XII, 1 g. of l7ot-methyl-l9-nor-A'landrosten-l7fi-olwas converted into the corresponding propionate.

In a similar manner, but using acetic, caproic and undecenoicarrhydrides as esterifying agents, there were obtained the acetate,caproate and undecenoate of 17w methyl-19-nor-A -androsten-1713-01.

We claim:

1. A process for the preparation of'a compound selected from the groupconsisting of A -androsten-17Bol and 19-nor-A -androsten-17,6-01comprising reacting a compound of the following formula:

A slow stream of purified acetylene Was intro- 7 consisting of hydrogenand a hydrocarbon carboxylic acyl group of less than 12 carbon atomswith one molar equivalent of bromine, reducing the thus formed 2abromocompound with a double metal hydride and reacting the thus formed2u-bromo-3,17 8-diol with zinc dust.

2. A compound of the following formula:

wherein R is selected from the group consisting of hydrogen and ahydrocarbon carboxylic acyl group of less than 12 carbon atoms and R isselected from the group consisting of hydrogen, lower alkyl, loweralkenyl and lower alkynyl.

3. 19-nor-A -androsten-175-01.

4. The acetate of 19-nor-A -androsten-17fl-ol.

The benzoate of 19-nor-A -androsten-173-01. 17 ot-methyl- 19-nor-A-androsten-17,3-ol. 17a-vinyl-19-nor-A -androsten-175-01.17a-ethinyl-19-nor-A -androsten-17 8-01. 17a-propargyl-19-nor-A-androsten-1718-01.

10A compound of the following formula:

wherein R is a hydrocarbon carboxylic acyl group of less than 12 carbonatoms and R is selected from the group consisting of lower alkyl, loweralkenyl and lower alkynyl.

11. The hydrocarbon carboxylic acid esters of less than 12 carbon atomsof A -androsten-17B-ol.

12. The propionate of A -androsten-l7 8-ol.

13. The valerate of A -androsten--ol.

14. The undecenoate of A -androsten-17fi-o1.

15. The cyclopentylpropionate of A -andr0sten-17fl-ol.

16. 17u-ethyl-A -androsten-17 3-ol-acetate.

17. 17u-ethinyl-A -androsten-175-01 acetate.

No references cited.

LEWIS GOTTS, Primary Examiner.

MORRIS LIEBMAN, Examiner.

2. A COMPOUND OF THE FOLLOWING FORMULA: